Tobacco smoking, which is attributed principally to the addictive properties of nicotine, continues to be a worldwide problem of drug abuse that leads to significant medical costs. Research investigating the mechanisms underlying nicotine dependence may provide insights into the development of behavioral and pharmacological approaches to the treatment of nicotine dependence and tobacco smoking. Similarly to dependence on other drugs of abuse, it is hypothesized that both positive and negative reinforcement processes play critical roles in the development and maintenance of dependence on nicotine. This project focuses on these two aspects of nicotine dependence in rats by exploring the neurobiological substrates of both the positive reinforcing properties of nicotine and the negative affective aspects of nicotine withdrawal that are hypothesized to lead to further drug use (i.e., negative reinforcement, self-medication). The overall hypothesis is that GABAergic and glutamatergic processes in the forebrain neural circuitry called the "extended amygdala" are critically involved in nicotine dependence. The proposed studies will explore the neurochemical substrates of acute nicotine reinforcement by investigating the role of GABA and glutamate neurotransmission in the reinforcing effects of nicotine, using an intravenous nicotine self-administration paradigm in rats (Specific Aim 1). Studies will also explore the role of GABA and glutamate neurotransmission in nicotine withdrawal as assessed by elevations in brain reward thresholds and somatic signs of withdrawal (Specific Aim 2). Finally, Specific Aim 3 will explore the brain sites that comprise or are related to the "extended amygdala" where GABAergic or glutamatergic manipulations may precipitate the affective and/or somatic signs of nicotine withdrawal. Preliminary work has demonstrated clear dissociations between reward threshold elevations and somatic signs of withdrawal that may be mediated by different brain sites. The experimental approach of studying the effects of GABA and glutamate neurotransmission with the same pharmacological manipulations in both the acute rewarding effects of nicotine and on nicotine withdrawal provides a cohesive, focused and well integrated research plan. The innovative aspect of this work is the emphasis on exploring non-cholinergic substrates of acute nicotine reinforcement and of the various aspects of nicotine withdrawal, with emphasis on the affective/reward aspects of withdrawal and the "extended amygdala."